G

lucocorticosteroids are commonly used

in veterinary medicine. Their uses are
broad ranging, but these drugs are
mainly used for their antiinflammatory and
immunosuppressive effects. There are consider-
able long- and short-term side effects associated
with administering these drugs; therefore, their
administration should be limited to specific con-
ditions in which their benefits outweigh their
risks. Neurologic diseases often require steroidal
therapy. The beneficial effects of steroidal ther-
apy, particularly regarding brain and spinal cord
disease, include protection from free radicals,
reduced intracranial pressure by decreasing pro-
duction of cerebrospinal fluid
(CSF), and maintenance of
normal microvasculature integ-
rity.
1
This article discusses the
specific uses and contraindica-
Article #3
ABSTRACT:
CE
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The main pharmacologic effects of glucocorticosteroids pertain to their antiinflamma-
tory properties, immunosuppressive effects, and potential tumoricidal role. Central nerv-
ous system (CNS) trauma involves multiple and complex pathophysiologic processes
that may benefit from corticosteroid administration. Unfortunately, clinical trials of these
drugs have not proven that they have a definitive or superior role in treating CNS
trauma. CNS inflammation may be infectious, but in many cases a specific pathogen is not
confirmed as the cause; in either case, patients may benefit from the actions of steroids
in the initial period. Other neurologic diseases, such as cerebrovascular disease, may not
benefit from corticosteroid therapy, whereas for some types of neurologic neoplasia, it
may be the only beneficial treatment available.
tions of glucocorticosteroids in veterinary neu-
rology based on experimental and clinical
research evidence.
PHYSIOLOGY AND MECHANISM
OF ACTION
Corticosteroids are primarily produced by the
zona glomerulosa (which produces aldosterone)
and zona fasciculata (which produces cortisol
and corticosterone) of the adrenal gland and
have a plethora of functions.
2
Corticosteroids
are constantly synthesized under the control of
the hypothalamus (via the effect of corti-
cotropin-releasing hormone on the pituitary)
and pituitary (via adrenocorticotropic hormone
[ACTH]). Cortisol and corticosterone concen-
trations in plasma influence ACTH secretion in
such a way that increased concentrations inhibit
release of ACTH and reduced concentrations
COMPENDIUM 210 March 2005
Administering Corticosteroids
in Neurologic Diseases
Simon R. Platt, BVM&S, DACVIM (Neurology), DECVN, MRCVS
a
Carley J. Abramson, DVM, DACVIM (Neurology), MRCVS
b
Laurent S. Garosi, DVM, DECVN, MRCVS
a
a
The Animal Health Trust, Centre for Small Animal Studies
Newmarket, Suffolk, England
b
The Ohio State University

stimulate release of ACTH.
3
Exogenous corticosteroid
administration can also suppress ACTH secretion, with
the degree of suppression depending on the particular
drug administered.
4
At least three steroid receptors have been identified
and associated with different physiologic effects.
5
Every
cell type has glucocorticosteroid receptors, with the type
and concentration of the particular receptor varying
between species and tissue.
3
Glucocorticoid receptors
are located in the cytoplasm of the target cell and are
inactivated until bound to a steroid ligand.
3
Steroids are
thought to enter the cell by passive diffusion; after they
have bound to the receptor, the glucocorticosteroid
receptor complex translocates to the nucleus, where it
binds to regulatory proteins of target genes.
3
Transcrip-
tion of the gene and subsequent formation of the tar-
geted protein is either induced or inhibited. The pro-
teins encoded by these genes are responsible for physio-
logic and hence pharmacologic effects of the glucocorti-
costeroids.
3
The natural function of glucocorticosteroids is to pro-
tect glucose-dependent cerebral functions by stimulating
formation of glucose by the liver, decreasing its periph-
eral use, and promoting its storage as glycogen.
2
Gluco-
neogenesis is the result of increased precursors and
induction of hepatic enzymes that catalyze reactions,
which are both necessary for glucose synthesis. In-
creased breakdown of proteins, particularly skeletal
muscle and collagen, provides gluconeogenic precursors.
This effect can be exhibited clinically as muscle wasting
and delayed wound healing. The metabolism of lipids is
also affected by glucocorticosteroids, which promote
lipolysis and inhibit long-chain fatty acid synthesis.
4
Glucocorticoids influence water and electrolyte balance
through mineralocorticoid actions. Synthetic glucocorti-
coids possess varying degrees of mineralocorticoid activ-
ity, but all have less than 1% of the mineralocorticoid
activity of aldosterone. Glucocorticoids also impart a
permissive effect on tubular mechanisms that maintain
the glomerular filtration rate; they have an inhibitory
effect on antidiuretic hormone and may decrease the
permeability of the distal renal tubules to water via a
direct action.
4
Glucocorticoids are most frequently used in clinical
medicine for their antiinflammatory and immunosup-
pressive actions. Their action is on leukocyte numbers as
well as function, ultimately impacting both humoral and
cell-mediated arms of the immune response.
2
Specifi-
cally, glucocorticosteroids inhibit the enzyme phospho-
lipase A
2
via lipocortin, which converts arachidonic acid
to prostaglandin and leukotriene metabolites.
2
Gluco-
corticoids also inhibit release of tumor necrosis factor
and interleukin-2 from activated macrophages. Tumor
necrosis factor induces cytotoxicity and can enhance
neutrophil and eosinophil function.
3
The immunosuppressive effects of glucocorticosteroids
are more pronounced on the cellular arm than on the
humoral arm of the immune system.
4
Glucocorticoids
have minimal effects on plasma immunoglobulin con-
centrations but can modulate immunoglobulin function,
inhibiting such processes as bacterial opsonization. The
immunosuppressive actions of glucocorticosteroids, like
their antiinflammatory actions, involve disruption of the
intercellular communication of leukocytes via inter-
ference with lymphokine production, biologic action,
or both.
3
The effects of glucocorticosteroids on the central
nervous system (CNS) are well documented. Indirectly,
glucocorticosteroids maintain adequate plasma concen-
trations of glucose for cerebral functions, maintain cere-
bral blood flow, and influence electrolyte balance in the
CNS.
3
In humans, glucocorticosteroids are believed to
influence mood (including euphoria), behavior, and
brain excitability.
3
The euphoric effect commonly recog-
nized in dogs is likely to reflect differences in glucocor-
ticosteroid receptors.
3
TRAUMA
Head Trauma
Severe head trauma is associated with a high level of
mortality in human and veterinary patients.
6
The appro-
priate therapy for head trauma patients remains contro-
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A definitive diagnosis of neurologic disease is often
required before glucocorticosteroid administration
can be advised in an appropriate regimen.
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Superoxide Radical Generation
Active kinases
and proteases
Xanthine dehydrogenase
Xanthine oxidase
(Reperfusion) 2O
2 + Xanthine + H
2
O
Uric acid
+
2H
+
+
2O
2
-
Figure 1. Reactive oxygen species such as the
superoxide radical (O
2

) are produced from xanthine

after a period of reperfusion. This reaction also requires the
enzyme xanthine oxidase, which is produced in the presence of
increased posttraumatic kinases and proteases.
Superoxide Radical Damage
CH
2
CH
2
CH=CH
CH
2
CH=CH
2
*
O
2
-
CH
2
CH
2
CH=CH
HC
*
CH=CH
2
+
*
O-OH
+
*
OH
CH
2
CH
2
CH=CH
HC-O
*
CH=CH
2
Figure 2. Representation of a phospholipid component
of a neuronal cell wall. Superoxide radicals (O
2

) attack
susceptible carbon atoms in the phospholipid, damaging the
structural integrity of the membrane and producing reactive
lipoxyl radicals and hydroxyl radicals (

OH), further propagating

the damage. (* = free radicals, C = carbon; H = hydrogen)
ing lipocortin production.
9
However, glucocorticoids
have actually been shown to potentiate neuronal damage
when ischemia is present; the reasoning behind this find-
ing may relate to the fact that corticosteroids make neu-
rons more vulnerable to metabolic insults, such as
cerebral hypoxiaischemia, by exacerbating the excitatory
amino acidcalcium cascade.
10
Corticosteroids have also
been shown to inhibit remyelination of injured neurons.
9
Despite the already mentioned advantages and en-
couraging results in laboratory studies, clinical trials
have failed to show a significant effect of glucocortico-
steroid administration on neurologic outcome or mor-
tality in humans with head injuries.
6,7
The Brain Trauma
Foundation and the American Association of Neurolog-
ical Surgeons developed a set of guidelines in 1995 for
patients with head trauma.
11
In this series of recommen-
dations, glucocorticosteroid administration was not ad-
vised for improving outcome or reducing intracranial
pressure in humans with severe head injury.
11
In a review
of 13 pooled steroid trials, there was an insignificant
(1.9%) reduction in deaths.
7
Another review of 2,295
humans with moderate or severe head injury demon-
strated no significant difference between corticosteroid
and control groups in the rate of the combined endpoint
of mortality and severe disability.
12
It has been suggested
that failure to demonstrate improved outcome with
steroid administration in patients with head trauma is
due to bias when recruiting patients into studies
13,14
and
versial because there have not been retrospective studies
focused on treating dogs and cats. However, it is agreed
that treatment should be immediate to allow patients to
recover to a level that is both functional and acceptable
to owners. Glucocorticoids have long been used in treat-
ing head trauma, and their administration is theoreti-
cal l y beneficial for many reasons. The most
well-documented benefit of glucocorticoids for nervous
system trauma is control of the so-called secondary
injury (i.e., inhibiting lipid peroxidation).
7
Secondary
traumatic brain damage is linked to alterations in funda-
mental neurochemical mechanisms that in turn produce
additional vascular and neuronal damage, thus impairing
the potential for recovery.
8
During posttraumatic metabolism, reactive oxygen
species are produced as a consequence of mitochondrial
dysfunction and as by-products of various enzymatic
reactions
8
(Figure 1). These reactive oxygen species are
responsible for lipid peroxidation, which plays a crucial
role in posttraumatic neuronal degeneration, and have
been linked to the prognosis of severe head injury
8
(Fig-
ure 2). The degree of reactive oxygen species
mediated oxidative damage is reduced by corticosteroid
administration in many experimental models of CNS
trauma; this research has led to the hope that gluco-
corticosteroids could help improve neurologic function.
8
Glucocorticosteroids also reduce cerebral edema forma-
tion and modulate the inflammatory response by inhibit-
recruitment numbers that are too small to demonstrate
small differences in outcome between groups.
12
This
issue has recently been addressed in the largest scale
investigation published to date, the Corticosteroid Ran-
domization After Significant Head Injury (CRASH)
study.
13
The CRASH trial involved over 10,000 patients
and was designed to determine the effects of short-term
corticosteroid infusion on death and disability following
significant head injury. The study demonstrated that the
risk of death from all causes, within 2 weeks of severe
head trauma, was actually higher in the group treated
with corticosteroids than in the placebo group.
Limited experimental evidence of efficacy exists for
administering a high-dose methylprednisolone sodium
succinate (MPSS) protocol to veterinary patients with
severe head injury. Therefore, routine administration of
glucocorticoids is not recommended for head injuries; in
addition, significant side effects may occur, such as
coagulopathies and hyperglycemia (which has an unde-
sirable effect on cerebral edema), together with an
increased incidence of infection.
1,6,7,12
Hyperglycemia
(>200 mg/dl) has been associated with increased mor-
tality in severely brain-injured humans.
15
The cause of
hyperglycemia and the reason for its severity during an
ischemic event are unknown and may well be a stress
response. Unless a veterinary study demonstrates a ben-
efit of corticosteroid administration in animals with
head injuries, a high-dose regimen cannot be advised for
canine or feline head trauma.
Spinal Trauma
The most common cause of acute spinal trauma in
dogs is thoracolumbar intervertebral disk disease, but
this also occurs as a result of external trauma such as
vertebral fracture and subluxation.
1
The severity of the
spinal cord lesion is influenced by the magnitude of the
disk protrusion and its rate of development. The com-
plex sequence of biochemical events initiated by any
trauma involves increases in the intracellular calcium
content, free radical production, and endorphin-associ-
ated ischemia. The vascular and biochemical events that
follow acute spinal trauma have been well reviewed.
1
Although medical therapies for spinal trauma are
numerous, experimental studies have suggested that sol-
uble glucocorticosteroids (e.g., MPSS) given within 8
hours of trauma may be beneficial.
16,17
MPSS is a gluco-
corticosteroid that has free radicalscavenging properties
when administered at very high doses.
18,19
The neuropro-
tective effect of MPSS may also be due to glucocorticoid
receptor-mediated inhibition of phospholipase A
2
.
20
However, MPSS has no effect on postinjury concentra-
tions of the products of phospholipase A
2
activation,
supporting the hypothesis that the neuroprotective
action of MPSS is mediated by free radical scavenging
rather than antiinflammatory actions.
21
A multitude of
experimental models of acute spinal cord concussion
have demonstrated that MPSS has a neuroprotective
effect when given at the time of or within minutes after
spinal cord injury.
1,20,21
A multicenter study in humans
also suggested that MPSS given within the first 8 hours
was beneficial.
16,17
In this study, MPSS was given at 30
mg/kg IV as a slow bolus and then at 5.4 mg/kg/hr IV
for the next 23 hours as a constant-rate infusion to
maintain a high level of the drug in the injured cord for a
longer period.
16,17
The clinically detectable benefits were
small but significant and involved both long tract and
segmental function.
22
These trials also demonstrated that
initiating MPSS treatment in patients with incomplete
injuries more than 8 hours after injury resulted in a
worse outcome.
17,22
It has been proposed that this is the
result of glucocorticosteroid interfering with normal
regeneration.
1
A more recent clinical trial in humans
demonstrated that if treatment with MPSS is initiated
within 3 hours of injury, a regimen that continues a
maintenance infusion of the drug for 24 hours should be
administered.
23
If treatment is initiated between 3 and 8
hours after injury, the infusion should be continued for
48 hours.
23
High doses of MPSS in acute spinal cord
injury have been associated with prolonged hospitaliza-
tion as a result of steroid-related side effects.
1,1523
In dogs, it has been suggested that MPSS be given as
an initial bolus of 30 mg/kg IV, with additional doses of
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Synthetic glucocorticosteroids have multiple physiologic and
pharmacologic actions that may be harnessed for multiple
benefits in managing specific neurologic diseases.
15 mg/kg IV at 2 and 6 hours after the initial dose and
thereafter every 8 hours for up to 48 hours after the
trauma.
1
However, these data have been extrapolated
from human and experimental literature because no
studies have been conducted to evaluate the efficacy of
such a regimen in veterinary patients. The most recent
canine experimental study showed that MPSS does not
provide a large or significant lasting benefit regarding
neurologic preservation or restoration.
24
This study
demonstrated a decrease in regional spinal cord blood
flow in association with MPSS therapy.
24
The recom-
mended regimen for cats based on experimental feline
studies is an initial dose of 30 mg/kg IV followed by 15
mg/kg at 2 and 6 hours and then an IV infusion of 2.5
mg/kg/hr for 42 hours.
19
This regimen has not been
clinically evaluated in this species.
If MPSS is administered too quickly to an awake ani-
mal, vomiting may occur, as may hypotension, especially
in traumatized patients. It is therefore advisable to
administer MPSS intravenously for approximately 5 to
10 minutes. Other side effects to consider are those
associated with the gastrointestinal (GI) tract.
25
A
recent study of dogs undergoing spinal surgery and re-
ceiving a single bolus of 30 mg/kg of MPSS followed by
a half to full dose 2 to 4 hours later reported that 90% of
the dogs developed occult GI hemorrhage.
1
Unfortu-
nately, many patients with spinal injuries that are seen at
referral institutions have already been treated with large
doses of steroidal or nonsteroidal drugs, which predis-
pose patients to adverse side effects (e.g., GI hemor-
rhage) and may influence the use and effects of MPSS
therapy.
Dexamethasone and prednisone have been extensively
administered at antiinflammatory doses to control the
inflammatory response to disk extrusion as well as to
reduce associated edema and improve local spinal cord
blood flow.
3
Administering these drugs to patients with
chronic disk disease (i.e., protrusion rather than extru-
sion) is unfounded in the early stages of the disease
based on the vastly different pathophysiology that
underlies compressive spinal diseases compared with
acute concussive disorders. Spinal cord blood flow and
oxygen levels can often be maintained when cord com-
pression occurs slowly; however, the ability of the spinal
cord to regulate blood flow to maintain homeostasis is
diminished.
26,27
The evident pathology in these cases is
predominantly demyelination and axonal swelling, and
only late in the course of the disease does the white
matter become edematous, which is vasogenic edema.
26
The edema itself is a cause of further compression
beyond that of the offending mass. Glucocorticosteroids
are effective in treating CNS vasogenic edema and have
been shown to be effective in treating spinal cord com-
pression, resulting in return of function without re-
moving the mass.
26
This explains the often dramatic
improvement in function with the initiation of gluco-
corticosteroid therapy occurring in patients with long-
standing spinal cord compression.
26,28
However, several
points should be emphasized:

Only short-term antiinflammatory regimens of pred-

nisone should be used. High-dose regimens should
not be used following an antiinflammatory regimen
when a patient with compressive spinal disease
acutely deteriorates because this favors GI ulceration.

Glucocorticosteroids cannot be advocated for early

compressive disease, especially when there is no diagno-
sis or there are no neurologic signs other than back pain.

The antiinflammatory effect of steroids can improve

the level of discomfort in these patients, encouraging
excessive activity levels in animals with spinal disease.

These patients should be considered for surgical

management rather than medical palliation once a
diagnosis is made.
INFLAMMATORY DISEASES
Infectious Meningoencephalomyelitis
The common infectious diseases responsible for in-
flammation of the brain and its structures in dogs are
canine distemper virus, rickettsiosis, and fungal and pro-
tozoal infections such as toxoplasmosis and neosporosis.
In cats, similar infections are detected, but neosporosis
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CNS trauma has a very complex and well-documented
pathophysiology whereby neurologic damage may be
progressive because of a secondary injury phenomenon.
Figure 3. Transverse T2-weighted magnetic resonance
cerebral scan of a 3-year-old female Maltese at the level
of the frontal lobes. The dog presented with seizure activity
and dementia.The diffuse hemispheric hyperintensity is suggestive
of an inflammatory lesion and was confirmed to be necrotizing
meningoencephalitis at the postmortem examination.
and rickettsiosis are less frequently reported. CNS dis-
ease with FIP is also seen in cats. Bacterial infections are
uncommon but can follow bacterial otitis media or in-
terna or a systemic septic focus such as prostatitis, par-
ticularly if steroids have been used to treat nonspecific
clinical signs of these diseases.
29
Distemper is not as
common as it used to be because of the success of vacci-
nation programs, but sporadic cases of distemper en-
cephalomyelitis in vaccinated dogs have occurred.
30
With this disease, there may be variable or temporary
success in halting neurologic signs in some dogs by
administering single, antiCNS edema doses of dexam-
ethasone (1 to 2 mg/kg IV).
30
Care should obviously be taken when administering
glucocorticosteroids to neurologic patients that may have
an infectious disease. The immunosuppressive properties
can cause severe extension of the disease; however, the
antiinflammatory effects of these drugs can be invaluable
when trying to reduce the clinical effects of infectious
damage to the CNS. For instance, in the case of rick-
ettsial diseases, although antiinflammatory and immuno-
suppressive doses of glucocorticosteroids slightly prolong
the duration of rickettsemia, they do not increase the
severity of the disease in experimentally infected dogs.
31
Treating cases of CNS FIP with glucocorticosteroids
would conceivably prevent clinical signs from progres-
sing, but immunosuppression might have the opposite
effect and precipitate a worse form of clinical FIP.
32
How-
ever, most successful treatments consist of relatively high
doses of immunosuppressive and antiinflammatory drugs,
including prednisolone (2 to 4 mg/kg/day PO).
32
For bacterial diseases in humans, dexamethasone
administered at 0.15 mg/kg 15 to 20 minutes before ini-
tiating antimicrobial therapy for up to 4 days seems to
lower intracranial pressure, CNS inflammation, and
neurologic sequelae.
33
A meta-analysis of randomized,
controlled clinical human trials conducted from 1988 to
1997 showed a beneficial effect of adjunctive dexa-
methasone therapy in bacterial meningitis cases and
suggested a protective effect if the drug was given before
or with parenteral antibiotics.
34
Unfortunately, no clini-
cal trials have been conducted to evaluate the efficacy of
steroidal therapy in canine or feline bacterial CNS dis-
ease, and so guidelines can be extrapolated only from
human data, which may not be appropriate.
Granulomatous Meningoencephalomyelitis
Granulomatous meningoencephalomyelitis (GME) is
the most well-documented sterile inflammatory disease
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of the nervous system, although the precise cause
remains unknown. The characteristics of the lesions
seen in patients with GME suggest a possible immuno-
logic basis for the disease, although it may not be one
disease entity.
35
Large perivascular accumulations of
mononuclear cells, predominantly CD3+ lymphocytes,
are often detected in the parenchyma and meninges of
the brain and spinal cord.
35
Adult small-breed dogs
(especially poodles and terriers) are predisposed to this
condition. Signs consist of acute or chronic onset of
ocular, focal, or multifocal neurologic deficits or signs of
meningitis; focal GME is described as having an insidi-
ous onset with a slowly progressive course, whereas the
disseminated form manifests with acute onset and rap-
idly progressive signs.
35
Definitive diagnosis is difficult
without histopathologic assessment of cerebral lesions
following biopsy; however, in confirmed cases, signs
often dramatically improve with an initial dose of pred-
nisone (1 to 2 mg/kg [preferably PO] bid).
35
The dose
should be tapered gradually to establish the minimal
effective dose. The prognosis for permanent recovery is
poor, and the overall response rate is variable.
36
The sur-
vival time for dogs with GME treated with corticos-
teroids ranges from 7 to longer than 1,000 days.
35
Necrotizing Meningoencephalitis
Necrotizing meningoencephalitis is a chronic progres-
sive disorder that has been documented in various forms
in pugs, Maltese, and Yorkshire terriers
37
(Figure 3).
Clinically and pathologically, this disease is identical in
pugs and Maltese; it affects dogs of both genders and
any age, causing an onset of seizure activity and general-
ized forebrain dysfunction, although a few animals may
exhibit brain-stem signs. The cause of this disease is
unknown, although the predominantly mononuclear
inflammation identified typically on CSF analysis sug-
gests a viral cause.
37
Histologic examination, which is
the only way to definitively diagnose this disease, can
confirm typical necrotizing lesions of the cerebrum with
disseminated meningitis, choroiditis, and cerebral
encephalitis.
37
There are several notable differences to
the presentation of this disease described in Yorkshire
terriers, including the fact that they seem to manifest
the disease as a chronic, slowly progressive dysfunction
of the fore- and hindbrain (often with cranial nerve
signs) and the lesions in the CNS are multifocal in the
cerebral white matter and brain stem. Administering
steroids has not been shown to have an effect on the
clinical course of the disease in any of these breeds,
Figure 4. Transverse T2-weighted magnetic resonance
cerebral scan of a 7-year-old boxer at the level of the
lateral ventricles and the parietal lobes. The scan
demonstrates a large, poorly demarcated mass of heterogenous
intensity (short arrow) with surrounding edema through the white
matter (long arrow).
although some patients may temporarily improve with
administration of prednisone (1 to 2 mg/kg/day).
37,38
Steroid-Responsive MeningitisArteritis
Steroid-responsive meningitisarteritis has been
reported frequently in large-breed dogsoften younger
than 2 years of age. Clinical signs are those characteris-
tically seen in patients with meningitis, including fever,
cervical pain, hyperesthesia, and pleocytosis of the
CSF.
39
Increased serum and CSF IgA levels have been
documented in this disease and are diagnostically help-
ful, although the causes of their intrathecal production
remain unknown. Attempts to isolate an etiologic agent
have been unsuccessful; therefore, an immunologic cause
is suspected. A small proportion of affected dogs may
also have idiopathic immune-mediated polyarthritis.
Affected dogs characteristically show dramatic improve-
ment in clinical signs when treated with immunosup-
pressive doses of corticosteroids.
39
It is recommended to
administer prednisone at 4 mg/kg PO q24h or IV for 48
hours, then 2 mg/kg PO q24h for 1 to 2 weeks, tapering
to 1 mg/kg q24h until the CSF is normal.
37,39
The glu-
cocorticosteroid dose can be slowly tapered over several
months. Long-term therapy is necessary in most cases,
and relapses may occur as the steroid dose is tapered.
However, the prognosis for resolution and at least a 2-
year remission of clinical signs with appropriate therapy
is excellent in over 50% of cases.
37,39
The elevated serum
and CSF IgA levels do not decrease to normal values
during prednisolone treatment, but pleocytosis can cor-
relate with the clinical signs.
37
NEOPLASTIC DISEASES
Although glucocorticosteroid therapy is deemed as
only minimal supportive care for all types of brain
tumors in the nervous system, it can often be necessary
and helpful. The aim of such treatment is directed at
controlling the secondary conditions of acquired hydro-
cephalus and peritumoral edema as well as reducing
associated intracranial pressure
40,41
(Figure 4). Gluco-
corticosteroids given at antiinflammatory doses can
reduce CSF production as well as vasogenic edema and
blood supply to the tumor within 24 hours.
42
Glucocor-
ticoids are believed to reduce tumor-associated vaso-
genic edema (Figure 5) by decreasing the pathologically
increased capillary permeability of the bloodbrain bar-
rier.
42
Glucocorticosteroids presumably act directly on
endothelial cells, reducing their permeability as well as
shrinking normal brain tissue, thus reducing overall
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intracranial pressure.
43
In humans with
brain tumors, there is no rigid schedule
for administering high-potency steroids;
the drugs are just administered at bedtime
to suppress headaches and focal signs and
are more successful for the former.
Although some clinicians prefer methyl-
prednisolone, dexamethasone is the gluco-
corticosteroid administered most often to
neuro-oncologic patients at empirically
chosen antiinflammatory doses initially
and up to four times daily.
42
There is no
reported consistently effective glucocorti-
costeroid regimen in veterinary medicine,
although we administer a parenteral anti-
inflammatory dose of dexamethasone
after an imaging diagnosis of neoplasia is
made while the patient is still under anes-
thesia; this is routinely followed by antiin-
flammatory doses of daily prednisone or
dexamethasone. Dexamethasone has been
preferred because of its low mineralocorti-
coid activity, which decreases the chance
of fluid retention. There have also been
studies suggesting that dexamethasone
may lower patient risk of infection and
impairment of the coagulation system
compared with other steroids.
42
Clinical signs improve in many pa-
ti ents wi th neopl asti c di sease when
steroids are administered. There are not
much data concerning the survival of
dogs or cats with brain tumors that have
received only steroids as palliative therapy. Results of
one study indicated a mean and median survival of 81
days and 56 days, respectively, following diagnosis via
computed tomography of primary brain tumors in
eight dogs.
44
Six of the eight dogs in this study died or
were euthanized within 64 days of brain tumor diag-
nosis. In another study, survival times from initial clin-
ical signs of the brain tumor to necropsy varied from 1
day to 405 days, with a mean survival time of 53
days.
45
When intracranial meningiomas were specifi-
cally evaluated recently, the median survival time from
diagnosis following steroidal therapy was 119 days.
46
Glucocorticoids can be administered at least 1 week
before intracranial surgery in brain tumor patients to
reduce cerebral edema and thereby facilitate cerebral
retraction for improved exposure.
47
Although clinical
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Normal
Astrocyte foot
Tight
junction
Capillary
endothelial cells
Cytotoxic
edema
Edematous capillary
endothelial cells
Edematous neuron
Edematous astrocyte
Vasogenic edema
Astrocyte
foot
Vesicular transport
across edothelial cells
Opened tight junctions
and escaping plasma
Figure 5. Representation of astrocytes and endothelial cells of the capillary
wall in the normal state, vasogenic edema, and cytotoxic edema. Heightened
permeability in vasogenic edema is due partly to a defect in tight endothelial junctions
but mainly to active vesicular transport across endothelial cells.The bottom diagram
represents cellular (cytotoxic) edema showing swelling of the endothelial, glial, and
neuronal cells at the expense of the extracellular fluid space of the brain.
data confirming the efficacy of this regimen are lacking
in veterinary medicine, we have been comfortable
extrapolating the perioperative indications and steroid
regimen from the human literature. If adequate surgical
decompression of the brain tumor is achieved, the
steroid dose can be tapered rapidly and discontinued
within the first week or two after surgery. Some patients
require steroid maintenance because a large volume of
tumor remains, tumor occupies the brain stem, or drug
dependence has resulted from long-term use. Patients
that no longer require glucocorticosteroids after surgery
may need them during or after radiation therapy. Reac-
tive edema may occur during irradiation, which may
cause transient clinical deterioration.
47
The lowest dose
of glucocorticoids that maintains patients at their maxi-
mum level of comfort and function should be used.
47
Figure 6. Transverse T2-weighted magnetic resonance
cerebral scan of a 2-year-old domestic shorthaired cat.
The image depicts bilateral symmetric, lateral ventricle
enlargement with third ventricular enlargement compatible with
hydrocephalus.
hydrocephalus may result in interstitial edema (i.e.,
increased water content of the periventricular white
matter) because of movement of CSF across the ventric-
ular walls. This may be secondary to increases in white
matter hydrostatic pressure or decreases in periventricu-
lar white matter blood flow.
48
Medical therapy for this condition does not usually
provide long-term resolution of clinical signs unless a
specific cause can be identified and resolved with treat-
ment.
49
Glucocorticosteroids can be administered to
decrease CSF production, thereby limiting intracranial
pressure and further neurologic injury.
48
Prednisone
(0.25 to 0.5 mg/kg PO bid) is recommended.
48
The
dose should be gradually reduced at weekly intervals to
0.1 mg/kg every other day.
48
The dose should be contin-
ued for at least 1 month and then discontinued if possi-
ble. Alternatively, dexamethasone may be administered
at 0.25 mg/kg PO q68h. The dose can be gradually
reduced over 2 to 4 weeks. Some animals can be ade-
quately managed with long-term glucocorticosteroid
administration at low doses. If no clinical benefits are
observed within 2 weeks or if side effects develop, other
forms of therapy (e.g., surgery) should be considered.
CEREBROVASCULAR DISEASE
Cerebrovascular disease is defined as an abnormality of
the brain attributable to a disturbance in its blood
supply.
4952
This can be diagnosed with the aid of imaging
techniques that are now more commonly available, such
as computed tomography and magnetic resonance imag-
ing.
5052
A stroke is a focal neurologic deficit of sudden
onset resulting from a cerebrovascular accident.
52
In dogs,
the cause of strokes can be classified as infarction (subse-
quent to blood vessel obstruction and ischemia) or hem-
orrhage (often secondary to blood vessel rupture).
52
Cerebral ischemia is reduction although not necessarily
cessation of blood flow to a level incompatible with nor-
mal function; the impairment may be global or regional.
52
Ischemia, viewed simplistically as hypoxia plus hypo-
glycemia, affects the most sensitive elements in tissue
and, if severe, persistent, or both, perturbs all compo-
nents. Severe ischemia, which in the CNS produces
necrosis of neurons and glial elements, results in an area
of dead tissue called an infarct. Much of the brain
swelling following an ischemic event is due to cytotoxic
edema, which is related to cell membrane dysfunction
49
(Figure 5).
Cerebrovascular accidents are characterized clinically
by peracute or acute onset of focal, asymmetric, and
COMPENDIUM March 2005
Administering Corticosteroids in Neurologic Diseases
218
CE
This is ordinarily determined by decreasing the dose
until signs increase or become apparent and then in-
creasing the dose until they subside. If deterioration is
secondary to tumor growth or treatment-induced ef-
fects, the glucocorticosteroid dose may have to be in-
creased to keep the patient comfortable.
Far fewer recommendations are available for adminis-
tering steroids to patients with spinal tumors; although
glucocorticosteroids are clearly indicated in treating
cord and nerve root compression, neither an optimal
dose nor the best schedule has been defined.
47
Current
recommendations for veterinary patients with neoplasia
affecting the spinal cord are extrapolated from the
human literature and include starting at high antiin-
flammatory doses and tapering to effect.
HYDROCEPHALUS
Hydrocephalus is the term commonly used to describe
abnormal dilation of the ventricular system within the
cranium (Figure 6). Ventricular dilation occurs in dogs
and cats because of a wide variety of intracranial disease
processes, often resulting in a form of stenosis of the
mesencephalic aqueduct or obstruction of the CSF
drainage pathways.
39
Hydrocephalus can result in clini-
cal signs from loss of neurons or neuronal function,
alterations in intracranial pressure, or associated patho-
physiologic effects of intracranial disease.
48
For example,
nonprogressive brain dysfunction.
49
Worsening of edema
(associated with secondary injury phenomenon) can
result in progression of neurologic signs for 24 to 72
hours. Hemorrhage may be an exception to this descrip-
tion, and patients may present with a more progressive
onset. Clinical signs usually regress after 24 to 72 hours;
this is attributable to diminution of the mass effect sec-
ondary to hemorrhage and reorganization or edema
resorption.
49
Administering glucocorticosteroids does not have a
positive effect on cytotoxic edema, can alter the size of
the infarction or hemorrhage, and probably does not
decrease intracranial pressure.
49
Although steroids are
often administered to decrease cerebral edema, their
benefit in cerebrovascular disease is questionable.
SUMMARY
Glucocorticosteroids have multiple physiologic and
pharmacologic effects that can be therapeutically bene-
ficial in CNS diseases. Although patients with many
neurologic diseases (e.g., cerebrovascular diseases) may
benefit from steroidal therapy, there is no substantial
clinical evidence for administering this therapy to
patients with these diseases. Many of the regimens for
administering steroids in neurologic disease have been
transcribed from human clinical trials, and there are no
similar trials in veterinary medicine. A definitive diag-
nosis is always required for specific steroidal therapy to
be maximally beneficial to patients without a risk of
side effects; however, because this is not often possible,
the likely benefits must be weighed against potential
detriments.
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CE
1. Where are glucocorticoid receptors located in
target cells?
a. cytoplasm c. nucleolus
b. nucleus d. Golgis bodies
2. In relation to aldosterone, how much mineralo-
corticoid activity do synthetic glucocorticoids
possess?
a. less than 1% c. 50%
b. 11% d. more than 71%
3. Reactive oxygen species produced immediately
after head trauma are responsible for
a. hypoglycemia.
b. hypoxemia.
c. lipid peroxidation.
d. hyperglycemia.
4. It has been recommended that soluble glucocor-
ticoids should be administered within ___ hours
after spinal trauma in humans.
a. 8 c. 15
b. 9 d. 18
5. One of the predominant pathologic changes
early in the course of spinal cord compression is
a. cytotoxic edema.
b. neuron cell body swelling.
c. interstitial edema.
d. demyelination.
6. What is the predominant cell type in the perivas-
cular lesions of granulomatous meningoen-
cephalitis?
a. neutrophils
b. CD3+ lymphocytes
c. eosinophils
d. mast cells
7. What is the proposed main mechanism of action
of glucocorticoids in reducing tumor-associated
vasogenic edema?
a. cerebral vasoconstriction
b. reduction of local intracellular calcium buildup
c. reduction of endothelial cell permeability
d. reduction of reactive oxygen species concentrations
(text continues on p. 228)
COMPENDIUM March 2005
228
8. What is the mean survival period of dogs with
nonspecific cerebral neoplasia (after clinical signs
appear) if treated with steroids alone?
a. 5 days c. 175 days
b. 59 days d. 275 days
9. Glucocorticoids purportedly help reduce clinical
signs associated with hydrocephalus by
a. increasing CSF absorption.
b. decreasing cerebral perfusion pressure.
c. causing cerebral vasoconstriction.
d. decreasing CSF production.
10. What type of edema, if any, is commonly associ-
ated with cerebral ischemic events?
a. interstitial
b. vasogenic
c. cytotoxic
d. none of the above
Administering Corticosteroids in Neurologic Diseases
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